1. Human Brain

2. Introduction nMechanisms of control of behavior u Reflex u Involuntary u Voluntary nUnderstanding from analysis of neural diseases

3. spinal cord n(and analogous brainstem) ndorsal root nventral root

4. Motor neurons neach a motoneuron innervates part of muscle nSize principle

5. Resistance reflex nexcitatory loop from muscle spindle

6. Schematic

7. Feedback from nmuscle spindle u intrafusal muscle fiber,  motoneuron u measures length u +ve loop to contracting muscle ngolgi tendon organ u in series u measures load u counteracts fatigue

8. Summary so far nReflex control of muscles u feedback and feedforward control u motoneurons in spinal cord (and analogous brainstem) u each a motoneuron innervates part of muscle u size principle

9. Motoneuron disease nAmyotrophic lateral sclerosis  motoneurons die nin 10-15%cases inherited, u chromosome 21 u superoxide dismutase (SOD) gene F 20% of cases F 120 mutations known

10. ALS treatment: none > 22% longer survival in mice

11. Descending control of motoneurons nfeedback and feedforward control u ff = anticipation nprimary motor cortex nsomatotopic map u neurons project to groups of muscles for coordinated act

12. Primary motor cortex

13. nstimulation gives movement nfire before voluntary movement Primary motor cortex

14. Role of brainstem nuclei nMajor pathway in voluntary movements u starts in association cortex u caudate and putamen F input from substantia nigra u globus pallidus u thalamus u ends in motor cortex

15. Circuit

16. Schematic circuit nfrom association (neocortex) to motor cortex

17. Huntington’s disease nsymptoms: faster jerky movements ngene for protein huntingtin (Htt) on chromosome 4 nmutates to include CAG (glutamine) repeats ngene repeats increase easily nHtt may disrupt synaptic transmission

18. Neural circuit ncaudate neurons [GABA] degenerate, u less inhibition of thalamus u increased excitation of cortex u more movement

19. Parkinson’s disease nsymptoms: hard to initiate and maintain movements (bradykinesia) ndeath of dopaminergic substantia nigra neurons ndying cells have Lewy bodies, u made up of neurofilaments u ubiquitin immunoreactivity

20. Lewy bodies nImmunoreactive to   -synuclein u ubiquitin  -synuclein may be misfolded nAdding ubiquitin to lys marks protein for degradation via proteasome

21. Parkinson’s disease nmimic with MPTP u 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine nmetabolise to MPP + u 1-methyl-4-phenylpyridinium nCauses ? u oxidative stress u glutamate toxicity u Parkin - fault in ubiquitination

23. Changes to circuit nmore tonic inhibition of thalamus ndecreased excitation of cortex

24. Therapy for Parkinson’s disease u L-DOPA u MAO-B inhibitors (selegiline = deprenyl) u cell replacement F fetal cells F stem cells u deep brain stimulation

25. Parkinson’s summary ndeath of dopaminergic substantia nigra neurons nhard to initiate and maintain movements (bradykinesia) u more tonic inhibition of thalamus u decreased excitation of cortex nmimic with MPTP (metabolise to MPP + ) ndopaminergic therapy ncells protected by Parkin

26. Summary so far nRole of basal ganglia is to combine with cortex to produce movement nNext: role of cerebellum

27. Anatomy of cerebellum

28. Inputs and outputs

29. Cell types nPurkinje cell u only output

30. Circuit nmossy fibers activate parallel fibers nclimbing fibers nPurkinje cells compare signals during movement with expected

31. Cerebellum nPurkinje cell (only output) nmossy fibers activate parallel fibers nclimbing fibers nPurkinje cells input synapses compare signals during movement with expected nmotor learning much reduced if cerebellum removed

32. Neural basis of reward nOlds & Miller 1954 nelectrical self- stimulation

33. Motivated movement nreinforcers + or - ndopaminergic neurons in u ventral tegmental area project to u nucleus accumbens F [and amygdala, DA & delusions]

34. Role of dopaminergic neurons nventral tegmental area project to u nucleus accumbens nfire during u feeding, u drinking u sex rat human

35. VTA pathway Dopaminergic A10 cell

36. Motivated movement II namphetamine (blocker of DA uptake) enhances reinforcement nreinforcement reduced by 6-OH DA or surgical lesions nelectrical stimulation of VTA axons (ICSS) reinforces

37. Addictive behaviour ntolerance to drugs ndependence nnormal mechanisms of learning “malfunctioning”

38. Addiction ncocaine down regulates DA receptors in nucleus accumbens nopioid [heroin] and ethanol activate neurons presynaptic to VTA ncannabis - modulates GABA inputs to NAC

39. Conclusion nmultiple mechanisms of control nintegration not yet well understood

40. Summary of Lecture nReflex control of muscles nDescending control of motoneurons nRole of brainstem nuclei in voluntary movement nMotivated movement and nucleus accumbens nAddictive behaviour